The vascular tree of humans is about 25,000 to 60,000 miles long through which 1000 to 2000 gallons of blood are pumped each day by the heart. In the outermost peripheral bifurcations of this tree--the microcirculation--a surface area is maintained for the exchange of nutrients and the drainage of waste products between blood and tissues. After tissue injury (by chemical, physical or biological agents), the sensitive local mechanisms regulating microvascular perfusion are impaired. Vascular patency is reduced, red blood cells adhere and stack up in a phenomenon called sludging, and blood contents leak into tissues. In severe injuries, especially in the respiratory tract, these changes in the microcirculation can distort tissue architecture, impede delivery of oxygen to cells, and cause extensive fluid loss from the vascular compartment resulting in life-threatening conditions such as lung edema, electrolyte imbalance, shock and other circulatory disorders. Thus, disruption of the microcirculation is harmful, especially when there is excessive leakage of blood contents into tissues.
Earlier views of tissue injury have sometimes focused upon the signs and the symptoms of inflammation, which is signalled by redness, swelling, heat and pain. A variety of chemicals have been implicated as chemical mediators of the inflammatory reaction, including histamine, serotonin, kinins, prostaglandins, platelet-activating factors, leukotrienes, and, from nerve endings, substance P. Mediators of the acute inflammatory reaction seem to play roles in one or more of increasing vascular permeability, attracting leukocytes, producing pain, local edema and necrosis.
A variety of physiologic responses occur from the biological events that constitute the inflammatory processes, and there are various steroid and non-steroid, anti-inflammatory drugs known to the art. In order to preserve vascular integrity, research and drug developments in this field have emphasized the discovery of drug antagonists on inflammatory mediators (substances that are released by injured tissues) that cause disruption of the microcirculation. In injured tissues, however, a number of inflammatory mediators are released.
U.S. Pat. No. ,801,612, inventor Wei, issued Jan. 1, 1989, discloses the use of inhibiting an inflammatory response in the skin or mucosal membranes of a patient by administering Corticotropin-Releasing Factor ("CRF"), or its analogs. CRF acts as an anti-inflammatory agonist. That is, CRF appears to be a substance that actively shuts off the response of tissues to virtually all known inflammatory mediators. The shut-off process may be triggered by agonist actions of CRF on epithelial cell-cell and cell-substratum endothelial binding sites that activate cell-cell, cell-substratum adhesion mechanisms so that the "tightening" of cell-cell, cell-substratum junctions and matrices prevent vascular leakage. CRF belongs to the corticoliberin superfamily.
Neurotensin is a 13-amino acid residue peptide first described by Carraway and Leeman in 1973. An 8-residue peptide, named xenopsin, was discovered in frog skin at about the same time by Araki et al. (1973). The neurotensin and xenopsin peptides are structurally related and affect various physiological functions such as blood flow (producing dilatation of blood vessels and a fall in blood pressure), digestion (these peptides increase the motility of the gut), temperature regulation (central injections of these peptides produce a fall in core temperature) and antinociception (administration of these peptides reduce motor responses to noxious stimuli). Neurotensin itself releases histamine from mast cells. U.S. Pat. No. ,926,756, inventors Leemah, issued Dec. 30, 1975, discloses the hypothalamically derived substance (and a synthetically prepared tridecapeptide) designated as "neurotensin." The biological activity of neurotensin was described by observing the vasodilation in rats, and was observed to cause a marked increase in vascular permeability following intravenous injection or intradermal administration. The octapeptide designated "xenopsin" having an amino acid sequence that is similar to neurotensin, is disclosed by U.S. Pat. No. ,928,306, inventors Uchiyama, issued Dec. 23, 1975. The octapeptide so designated depresses blood pressure and causes stomach muscle contractions.
Foreman et al. studied an interaction of neurotensin with substance P, and suggested that neurotensin is a partial agonist at the substance P receptors on rat mast cells, and in human skin. Br. J. Pharmac., 77:531-539 (1982). Antagonism of substance P, however, does not indicate or constitute full efficacy as an anti-inflammatory agent on injury-induced vascular leakage.
Some other members of the neurotensin family, all of which are strikingly similar in their C-terminal regions, are described by Carraway and Reinecke in their article "Neurotensin and Related Peptides", which appears as Chapter 4 in The Comparative Physiology of Regulatory Peptides (Holmgren, editor, Chapmann & Hall, London, 1989). As noted by Carraway and Reinecke, structure and function studies have indicated a strong dependence on the five or six residues of the C-terminal portion for neurotensin and related peptides, and it appears that the C-terminal portion of these peptides is highly conserved in evolution.
Despite the studies of various biological activities for neurotensin and peptides related to neurotensin, no researchers have reported that neurotensin, and related peptides act as anti-inflammatory agonists and, like CRF, actively shut off the response of tissues to virtually all known inflammatory mediators. Instead, neurotensin has been generally thought to be a promoter of vascular leakage in the circulatory system or has generally been thought to be an inflammatory mediator.